Maintenance of cognitive function in old age has become increasingly desirable to a human society with an aging population. Various studies have shown that there is major variation in the clinical manifestations and severity of cognitive aging as a result of neurodegenerative changes that are similar in nature and extent. These mismatches led to the emergence of the concept of cognitive reserve (CR), which focuses on the adaptability and the flexible strategies of the brain that allow some people to cope better than others in the circumstance of age-related or Alzheimer's disease (AD)-related pathology. It is believed that CR is mainly influenced by an individual's education, intellect, mental stimulation, participation in leisure activities, dietary preferences, and social stimulation. These determinants of CR help in slowing the rate of memory decline in the normal aging process and also reduce the risk of developing AD. The role of functional neuroimaging has recently gained importance in the context of understanding the neural basis of CR and its relationship to aging-related behavior changes. Future research in this field may enable earlier detection and thus reduction in the prevalence of age-related cognitive changes and AD. This article is a review of the neurobiology of CR, the concept of CR, and the promotion of preserving CR by analyzing its determinants along with their implementation against its deterioration toward cognitive loss and disorders.

"Animal life on earth goes back millions of years, yet most species only use three to five percent of its cerebral capacity. But it isn't until we reached human beings at the top of the animal chain that we finally see a species use more of its cerebral capacity."

- Professor Norman (Morgan Freeman) in the film Lucy (2014)

Various studies over the past three decades have demonstrated that the pathology of Alzheimer's disease (AD), stroke, and traumatic brain injury (TBI) and their clinical symptoms are not tightly linked. This gave rise to the hypothesis of brain reserve capacity (BRC). According to the hypothesis, once the BRC crosses a fixed critical threshold, specific clinical symptoms and functional deficits start emerging. This model recognizes that there are individual variations in BRC that give rise to varied clinical expressions of brain damage. This concept of the reserve can be classified into passive and active models. [1]

Brain reserve - "The hardware"

Brain reserve (BR) is an element of the "threshold model" or the passive model. According to this model, there is a fixed threshold value at which functional impairment manifests for everyone. The brain's size, the neuronal count, and the synaptic density form the basis of BR. [2],[3] Larger brains, due to sufficient neural substrate, are able to sustain more insult till symptoms emerge. A brain insult of a particular size might cause a clinical deficit in an individual with less BRC, whereas it may not cause any deficit in individuals with greater BRC. Thus, these models are essentially quantitative models. They state that the individual variation is seen only in their brain capacity and that brain damage is either sufficient or insufficient to deplete BRC to a certain critical level. When synaptic density falls beyond a critical point, the initial symptoms of cognitive impairment appear. This implies that the loss of neurons must be very severe in individuals with more BR for the symptoms to appear later.

In AD, the threshold value might mean the depletion of synapses to a point where only a specific number of synapses remain. Graves et al. stated that persons with AD with a smaller head circumference would have cognitive deterioration more rapidly than those with larger head circumference. [4] The study emphasized the importance of environmental factors in prenatal and early life that influence the completed brain/head size and, in the long run, determine the expression of AD in vulnerable individuals in late life. In a study on 649 subjects, Schofield et al. showed that old people with smaller head sizes were more likely to have AD, and thus premorbid brain size may have an influence on the age-specific risk for AD. [5] Thus, individuals with larger brain size would have more neuronal volume to lose before the critical threshold is reached. However, this passive model has been investigated, with conflicting results. Jenkins et al. showed that larger head size did not help in delaying the onset of AD. [6]

Cognitive reserve - "The software"

Cognitive reserve (CR), on the other hand, constitutes the active model, according to which the brain copes with damage by using either preexisting cognitive processes to increase the efficiency and capacity of existing neural pathways or by using compensatory processes to recruit new pathways that are usually not used while accomplishing a task. [7] Thus, a person with a greater CR may be able to sustain a larger lesion than a person with lesser CR before clinical symptoms start appearing, even though both may have the same BRC. This type of an active model of reserve is subdivided into two components, neural reserve and neural compensation. [1],[3] The neural reserve comprises the interindividual differences in cognitive processing that usually preexist in the normal, healthy human brain, whereas neural compensation refers to the alterations in cognitive processing that may take place in order to cope with brain pathology.

Determinants of cognitive reserve

Numerous studies have pointed toward a variety of lifestyle factors that may influence CR by encouraging positive neuroplasticity. These in turn have an effect on cognitive functioning as well. These determinants or causative factors include cognitive stimulating activities, cognitive remediation, level of education, leisure activities, social stimulation, diet, good sleep, hygiene, and physical activity in early life.

Cognitive engagement and stimulating activities

Many studies state that cognitive stimulation as a lifestyle variable slows cognitive decline in people who routinely engage in cognitively demanding tasks when compared to those who do not. In a study of 65 healthy older individuals, it was found that individuals with greater early and middle life cognitive activity (reading, writing, playing games, physical exercise) had lower Pittsburgh Compound B (PiB) on positron emission tomography (PET) scan studies. [8] The study found that lifestyle factors found in individuals with high cognitive engagement may prevent or slow the deposition of β-amyloid, resulting in slower progress to AD.

Another measuring factor of cognitive engagement could be bilingualism. Schweizer et al. studied a number of linear measurements of brain atrophy from computed tomography (CT) scans of monolingual and bilingual patients who were diagnosed with probable AD. [9] They reported greater amounts of cerebral atrophy in bilinguals than in monolinguals, in areas of the temporal horn, hypothesizing that bilinguals required greater amounts of neuropathology before the disease manifested.

A recent study examined cognitive differences between older healthy subjects based on the extent of instrumental musical experience across the life-span. [10] It revealed significant differences between high-activity musicians and nonmusicians on measures of naming, nonverbal memory recall, visuomotor speed, visuomotor sequencing, and cognitive flexibility. Cognitive functioning in old age was found to have a linear relation to the number of years of musical participation.

A Chicago (Illinois, USA)-based study on 823 older people without dementia was carried out to check for the relation between social isolation and risk for cognitive decline. The risk of AD was found to be more than double in lonely persons as compared with those who were not. [11] A meta-analysis on 135 studies showed a positive association between cognition and three key measures: Educational level, occupational status, and cognitive stimulating activities, the latter two showing the most variation. [12]

Cognitive remediation

Cognitive remediation is an emerging concept in the field of CR and aging. In older adults, it is observed that there is a decline in the executive control functions. The goal is to slow and reverse these changes. It is a behavioral treatment that aims to enhance the compensatory and adaptive strategies to facilitate improvement in specific brain areas such as attention, memory, judgment, speed of information processing, and problem solving. The training activities consist of computerized exercises and real-time strategy-based video gaming. This treatment is reported to enhance executive functioning in the elderly. In a study conducted at the Beckman Institute at the University of Illinois, 40 older adults were divided into two groups, of which one group was randomly assigned to the training condition of a real-time strategy video game. [13] The researchers attempted to train the executive functions in the form of working memory, task switching, short-term memory, inhibition, and reasoning. The trained older individuals improved significantly more than the controls.

Education

Education may indirectly help in increasing the CR by reducing the impact of neuropathological lesions during aging. Even a few years of formal education is associated with decreased impairment in cognitive functioning as compared to no formal education at all, irrespective of the socioeconomic and demographic characteristics of a population. [14] There is a dose-effect relationship between education (years of schooling) and cognitive impairment. The higher the level of schooling, the less the cognitive decline. An autopsy study was done at the London Health Sciences Centre University Campus of the University of Western Ontario on 87 patients with AD, dementia with Lewy bodies, or both. The study found that though higher education does not modify the course of AD, lower education was related to increased occurrence of cerebral infarcts, suggesting a "brain battering" model. [15] Various studies have found that those with higher education are able to compensate for the pathological burden in later life, whereas those with lower education have an increased vulnerability to cognitive deterioration. [16],[17],[18]

However, there are conflicting studies reporting the relationship between lower education and age-related cortical atrophy, with some studies in favor of it and [19] some rejecting the association. [20] In the famous "Nun Study," (Mortimer et al., 2003), the individuals having both low education and smaller head circumference were four times as likely to suffer from dementia as the rest. [21] The study also stated that higher education and larger head size alone or in combination may reduce cognitive decline in later life.

In a study conducted at the John Hopkins School of Medicine, Baltimore (Maryland, USA), 769 patients with moderate to severe TBI were analyzed. It was found that people who had attained a higher level of education had stronger recoveries than those who had not. [22] A new study from Sweden shows that children who get good grades in school and later work in complex jobs that involve data and numbers may be protected from developing dementia later in life. These childhood school grades act as a marker for "early-life cognitive abilities."

Role of leisure activities

Various epidemiological studies have demonstrated that late-life mental stimulation activities are reported to aid in better cognitive functioning. [23],[24],[25] In a population-based study of Chinese people aged 65 years and older, participation in leisure activities was found to decrease the risk of subsequent cognitive decline over a period of 2.4 years of follow-up. [26] The cognitive decline was measured against three main domains: Mental activity (global cognition, language, and executive function), physical activity (memory and language), and social activity (global cognition). It was found that all the types of activities protected against cognitive decline in women. However, only mental and physical activities were associated with decreased cognitive decline in men. The study concluded that the more the types of activities, lesser was the cognitive decline found.

Various life experiences have an influence on neural processing and synaptic organization. These permit various neurological processes to become adaptive and more efficient, thus allowing the individual to cope with the neurodegenerative pathology of progressive dementia. [2],[3] The CR hypothesis postulates that such life-span experiences offer protection from AD pathological insults such as neuroplasticity, neurogenesis, and locus coeruleus-noradrenergic (LC/NA) system. [27]

Cognitive functioning is also improved by leisure activities that lower stress and help the individual in living a healthier lifestyle. They have a beneficial effect on cardiac and cerebrovascular diseases as well. It also helps in reducing the risk of infections, affecting the body's immune system by having an antiinflammatory effect and promoting psychological well-being. In a study of 107 same-sex twin pairs, participation in leisure activities during early and middle adulthood was studied for risk of AD. [28] The study found that individuals who engaged more with others had less cognitive decline as a result of positive emotional states and lower stress. Thus, exposure to leisure activities results in chronic neuronal activation secondary to increased brain metabolism, increased glucose and oxygen consumption, and increased cerebral blood flow. It may also help in increasing synaptic density in the neocortical association cortex. [2],[3]

Social network and stimulation

Social support and networking provide psychological and material resources that are usually intended to benefit an individual's ability to cope with stress. Especially in a country such as ours, the setup of a joint family is vital for providing social support to the elderly. A number of social parameters such as marital status, number of children, frequency of meeting family members and relatives, living arrangements, and satisfaction with life have been studied. Other variables such as attending social functions, participating in religious activities, and having a part-time or full-time job are equally important. Bennett et al. studied 89 elderly people as a part of the Rush Memory and Aging Project to study the effect of social networks in modifying the effect of Alzheimer's pathology in the brain. [29] During the brain autopsies, amyloid load and the density of paired helical filament tau tangles were quantified with antibody-specific immunostains. The CR helped maintain cognitive capacity in participants with larger network sizes, even at more severe levels of global disease pathology.

However, there are also a few studies that show no association or minimal association between social networks and cognitive decline. [30] Similarly, cultural factors, especially in our country, should be taken into account. Joint families are a source of larger social networks than nuclear families.

Nutrition

Studies have shown that poor nutrition at an early age can increase the likelihood of cognitive deficit in later life. [31] Though it is still not known exactly how increased oxidation and increased inflammation correlate with age-related cognitive declines, nutritional supplementation has been shown to decrease age-related reactive oxygen species (ROS) production and to increase synaptic plasticity, learning, and memory.

Vitamin D deficiency is associated with a significant effect on cognitive performance in old age. [32] Deficiencies in folic acid, vitamin B 12 , and vitamin B 6 are related to cognitive impairment in late adult life due to elevated plasma homocysteine levels. [33],[34] In addition, diets high in Ω-3 chain polyunsaturated fatty acids (PUFA) known as docosahexaenoic acid (DHA), such as fish oils (salmon, sardine, tuna, etc.) may protect people from cognitive decline and dementia. [35] Amino acids, especially L-carnitine, are shown to increase cognitive capacity by reducing fatigue and improving cognitive functions. [36]

Royal jelly facilitates neurogenesis in the hippocampal dentate gyrus, which is largely responsible for regulating the number of granule cells involved in cognitive ability. [37] Curcumin, the natural pigment that gives the spice turmeric its yellow color, is shown to be effective against learning and memory deficits, and its neuroprotective effect was suggested to work as a result of normalizing the corticosterone response, resulting in downregulation of the pCaMKII and glutamate receptor levels. [38] Similarly, Withania somnifera (Ashwagandha or the Indian winter cherry), a famous herb in the Indian Ayurvedic system of medicine, is reported to have a cognition-promoting effect, especially after head trauma. [39] Adherence to the Mediterranean diet, which is a plant-based diet characterized by a variety of fresh fruits and vegetables, grains, and plenty of fish, is associated with slower cognitive decline. [40]

Recently the nutraceutical NT-020, containing a formulation of blueberry, carnosine, green tea, vitamin D, and Biovin, was reported to induce modest improvements in cognitive processing, by creating a synergistic effect that promotes the proliferation of stem cells in vitro and in vivo. [41]

Early-life situations and physical activities

Significant effects of early-life conditions on the absolute level of cognitive function in old age have been noted, complementing the existing literature by extending these observations to an older population. [42] The results from this study suggest that socioeconomic and cognitive conditions in early life contribute to absolute levels of cognitive function but do not protect against cognitive decline in later life. Physical activity and cognitive decline are inversely related. A few studies have suggested that early-life physical activities may actually delay late-life cognitive deficits. [43] In a study of 6434 subjects aged 65 years and older, it was found that compared with no exercise in early life, physical activity was associated with lower risks of cognitive decline and dementia. [44] In another prospective study of 1740 people older than 65 years without any cognitive impairment, the incidence rate of dementia was only 13 per 1000 person years for those who exercised >3 times per week as compared to 19.7 per 1000 person years for those who exercised <3 times per week. [45],[46]

Sleep

Sleep changes profoundly as age advances, being characterized by more sleep deprivation, earlier awakening, and less slow sleep. A recent study of 2822 older men reported a correlation between poor sleep quality and the development of cognitive decline. [47] Higher levels of fragmented sleep and lower sleep efficiency were associated with a 40-50% increase in the odds of clinically significant decline in executive functioning, equivalent to the effect of a 5-year increase in age. Among older men, reduced sleep efficiency, greater nighttime wakefulness, and greater number of long wake episodes (LWEPs) were associated with subsequent cognitive decline. However, daytime sleepiness and duration of sleep were not related to subsequent cognitive decline. Sleep deprivation studies in healthy young adults found sleep deprivation to have an effect on executive functioning in old age. [48]

Future and promotion

The concept of healthy and successful aging has gained momentum in the last two decades, especially after the breakthrough provided by the Nun Study with the School Sisters of Notre Dame religious congregation. More insight in identifying the neuropathological correlates of healthy aging may help identify the determinants of healthy aging.

Measurement of CR

The first attempt to measure CR was made by Shallice and Evans (1978), [49] who developed the Cognitive Estimation Test, which consisted of a set of questions requiring appropriate reasoning abilities; it was later revised by Macpherson et al. (2014). [50] A cognitive estimation task involves: A central processing control, which defines the appropriate strategies to solve the problem; the working memory, which applies these strategies; and long-term declarative memory, where the necessary information for answering the task is stored. Another method is the Cognitive Rating Scale (CRS), a new test that measures participation in cognitively stimulating activities throughout a person's lifetime. [51] In 2011, Nucci et al. developed the Cognitive Reserve Index questionnaire (CRIq) to quantify the amount of CR accumulated over one's lifetime. [52] It has 20 items grouped into three sections: Education, working activity, and leisure time. The Memory Binding Test (MBT) developed by Herman Buschke measures "associative binding" through two category word lists that people are asked to remember and thus can be used as a cognitive marker. [53] Recent research has pointed toward the influence of personality traits on the cognitive abilities of individuals. The Neuroticism-Extraversion-Openness Personality Inventory-Revised (NEO PI-R) personality questionnaire covers the domains of neuroticism, conscientiousness, agreeableness, extraversion, and openness to experience. Individuals with a neurotic personality type may have reduced brain plasticity during the performance of working memory tasks that may affect their cognitive abilities. [54] A novel concept called the "cognitive footprint" (drawn from analogy to "carbon footprint") is proposed, which aims to identify and develop the cognitive abilities of an individual right from birth and maximize their lifetime contribution to society's "cognitive capital." [55] Research is also directed toward neuroimaging [functional magnetic resonance imaging (fMRI), PET scan, etc.] to identify the brain networks associated with CR-related activation. [56]

Future implications

The role of bilingualism in delaying the onset of AD is a matter of research; more studies are required to understand the underlying mechanism and to rule out any confounding factors, including education and occupational status, especially when immigration is so common in today's world. In addition, the prevalence of cognitive disorders should be studied on a larger scale in countries with high rates of bilingualism, such as India. Future research in cognitive remediation, especially in video game training and other training modules, should look for any improvement in task performance in everyday cognitive tasks in the real world such as sports, driving, multitasking, and leisure activities, and in other cognitively demanding fields. Multitasking is of real value in today's world as various research studies have shown how it can be shaped through various cognitive training tasks, making it one of the most important focuses of research. These tasks could be refined according to the specific type of cognitive decline. However, research is also warranted to identify how long this effect of cognitive remediation works.

The effect of leisure activities in enhancing the CR has been proved in various studies. Thus, individuals should be exposed to more enriched environments, comprising not only social interaction but also more physical activities. Taking part in social activities, walking or going for an excursion, reading, visiting friends and relatives, going to restaurants, movies, etc. should be encouraged for the elderly. More engagement in such activities may ultimately help individuals build a reserve, making them resilient and efficient in the face of pathological changes in the brain.

The role of social functioning in slowing cognitive decline could help in devising better social and health-related policies and practices, ensuring a better quality of life in the elderly. However, more research is needed to understand this causality, whether social networking has a protective role or it is that people without dementia are able to maintain their social networks for a longer time than those affected. More so, the role of social networks in enhancing and maintaining the CR in the Indian context is somewhat unclear and worthy of study. In Indian society, where the majority still live in villages, a different approach should be adopted in looking into social networks that are culturally acceptable and more supportive toward the elderly.

A recent study has shown beneficial effects of cochlear implants in rehabilitation of elderly by improving speech perception and cognitive abilities, thus positively influencing their social activity and quality of life. [57] Stem cell research appears to be the field for major development in the field of cognitive disorders and it certainly looks promising. The neuroprotective effects of the stem cells mediated through neurotrophins, mainly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), stimulate survival of neurons and aid synaptogenesis. [58] The latest research at the University of California, San Francisco involved the discovery of an RNA molecule called Pnky that regulates neurogenesis from neural stem cells in the embryonic and postnatal brain. This may open the doors for regenerative medicine in treating neurodegenerative disorders such as AD, Parkinson's disease, and TBI. [59]

Findings from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, long-term, randomized controlled trial, suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population. [60] Studies have shown that higher CR was associated with diminution of age-related alterations in cerebrospinal fluid (CSF) biomarkers such as Aβ42, total tau (t-tau), and phosphorylated tau (p-tau). [61] The inclusion of such biomarkers will certainly help such models in the long run. The University of Minnesota is planning a sequel to the Nun Study under Dr. Kelvin Lim, which will be a higher-tech version of the first study, using advanced neuroimaging and genetic tests to study the process of cognitive aging.

With the recent advances in treatment modalities for cardiovascular diseases and cancer, the world will see a growth in the elderly population in the next few decades. The CR hypothesis points toward difficulties in diagnosing patients with AD and other neurodegenerative diseases until later in their course. Hence it would be wiser to implement the findings of various studies that have been reviewed in this article and to encourage aging patients to actively engage in cognitively stimulating activities and live in a socially enriched environment in order to experience a disease-free natural life-span.

Conclusion

Thus, to conclude, the endowment of the brain to humans manifests by a structural BR (the hardware), with its enhancers and decliners having limitations, as seen in [Figure 1], but may change as its concept evolves in the future. The manifestation of the functional brain is CR (the software) with its enhancers and decliners. In this interaction, CR appears to be more important than BR for changing and manipulating through various techniques. In spite of the limitations found in assessing BR, the ways and means of evaluating and modifying CR will be the focus of cognitive research in future." A positive outlook on life may not only help you live longer and prevent you from having a disease, but even if you do have the disease you may not be as affected by it as your less optimistic and less cheerful counterparts."

Singh RH, Udupa KN. Clinical and Experimental Studies on Rasayana Drugs and Rasayana Therapy. New Delhi: Special Research Monograph, Central Council for Research in Ayurveda and Siddha (CCRAS), Ministry of Health and Family Welfare; 1993.